Understanding the mechanisms of pain signaling and control of pain has become a national health priority as evidenced by the recent mandate from Congress that established 2001-2010 as the "Decade of Pain Control and Research." To understand how pain develops and is maintained, we are studying the development, phenotype and physiologic properties of primary sensory neurons that project to the skin and respond to painful stimuli (nociception). The role of target-derived artemin in nociceptive system development and function will be determined using a multifaceted approach that includes behavior, anatomy, electrophysiology and molecular biology to define how artemin dependent neurons function in perception and processing of pain stimuli. An established transgenic expression system and ex vivo nerve-skin preparation that allows for comprehensive analysis of individual sensory neurons will be used in this analysis. The long-term objective of this research is to understand how growth factors regulate the development and properties of neurons that transmit painful stimuli. The Specific Aims are to: 1) Test the hypothesis that skin-derived artemin is a survival and differentiation factor for specific types of nociceptor neurons, 2) Test the hypothesis that artemin responsive neurons have a comprehensive phenotype (CP) distinct from NGF-dependent and GDNFdependent nociceptor neurons, and 3) Test the hypothesis that enhanced levels of artemin modulates behavioral response properties following inflammatory and neuropathic pain stimuli. These experiments will use anatomical and immunohistochemical analysis, ELISAs, reverse transcriptase PCR assays, electrophysiological recording and characterization of single afferents and behavioral testing to define the role of the artemin growth factor in development of sensory neurons and the role of these neurons in pain transmission.